Executive summary and research policy recommendations

2013 HIV pipeline executive summary

The 2013 HIV pipeline comprises adult and pediatric antiretroviral therapy (ART) development and dose-optimization research as well as antiretroviral preventive technologies, research toward a cure, and immune-based and gene therapies.

Adult and pediatric ART clinical research continues to move forward robustly, with encouraging movement on the dose-optimization front. In 2012, for the first time, the U.S. Food and Drug Administration (FDA) approved the use of an antiretroviral combination, emtricitabine/tenofovir DF (FTC/TDF, Truvada) as preexposure prophylaxis (PrEP) for sexual transmission of HIV.

HIV vaccine research made encouraging progress in basic science, while clinical trials continued to experience setbacks, which moved the field back toward early-stage, preclinical, and phase I activities.

Cure-related research moved forward slowly but with encouraging surprises, while immune-based and gene therapies—many of them now being drawn into the cure-related space—remain promising but unproven for individuals with suboptimal immune responses despite viral suppression (so-called immunologic nonresponders, or INRs) and for those with HIV-related immunologic senescence and inflammatory end-organ disease.

Adult Antiretroviral Pipeline

The three themes of the “Antiretroviral Pipeline” by Simon Collins and Tim Horn [1] are the continuing wave of innovations bringing broader and in some cases better treatment options for people with HIV; the possible conflicts these innovations will encounter due to global economic austerity; and the potential for combining generic antiretrovirals as they move off-patent in many developed countries with innovator compounds to produce synergistic, often cross-sponsor, combinations and fixed-dose combinations (FDCs) that could offer people with HIV the best of the new and the old while saving cash-strapped health systems billions of dollars.

The 2013 adult ARV pipeline is robust, with one drug, dolutegravir, awaiting FDA expedited review in August 2013, two 2012 submissions, elvitegravir and cobicistat, still undergoing extended review, and a triple fixed-dose single-pill once-daily combination of dolutegravir, abacavir, and lamivudine (3TC) following rapidly on the single drug in the pipeline.

Three compounds covered in previous pipelines, apricitabine, ibalizumab, and PRO 140, are stalled, generally awaiting outside investment from a new sponsor, while one compound, the NNRTI lersivirine, was terminated in February 2013.

Last year, Gilead secured a first-ever FDA approval of an FDC containing two new drugs, the integrase inhibitor elvitegravir (EVG) and the pharmacokinetic booster cobicistat (COBI) with two approved ones, FTC/TDF, in the quadruple single-day pill branded as Stribild. This apparent slam-dunk was mitigated by the U.S. federal HIV treatment guidelines’ relegation of the new FDC to an alternative first-line regimen due to concerns about efficacy and tolerability in comparison with preferred first-line regimens containing boosted atazanavir or darunavir, efavirenz, or raltegravir in combination with FTC/TDF; [2] and by the FDA’s decisions in early 2013 to defer approval of both new single agents, EVG or COBI, as single drugs due to unspecified concerns with their dossiers. [3, 4] Gilead’s FDC-first strategy was clever, but may foreshadow an unfortunate tendency on the part of some sponsors to privilege combinations from their own companies, which may not be those best suited for individual patient management.

This year’s leading compound for FDA approval, the integrase inhibitor from ViiV known as dolutegravir (DTG), demonstrates many advantages over the other two approved agents in its class, including a low molecular weight permitting once-daily 50 mg dosing in treatment-naive patients, and no food or pharmacokinetic boosting requirements. The sponsor’s impressive data report superiority to Atripla (efavirenz/FTC/TDF) in treatment-naive patients, noninferiority to raltegravir (RAL) in the same population, and interim results reported at CROI 2013 in treatment-experienced, integrase-naive patients report greater viral suppression on DTG vs. RAL. [1]

The development plan is progressive with respect to key drug-drug interaction studies such as those with methadone or combined oral contraceptives (already complete), a pediatric development plan (already under way), and the sponsor’s already-undertaken negotiations with generic manufacturers to make the product available globally at accessible prices in low- and middle-income countries (LMICs). [1]

Collins and Horn warn, however:

The model of pricing newly approved antiretrovirals (ARVs) higher than current drugs is increasingly difficult to sustain….The demand for ARVs is well established and it will continue to expand for many years: life expectancy has been dramatically extended; treatment is lifelong and is now being recommended [in rich countries] regardless of a person’s CD4 T-cell count; rates of new infections and diagnoses remain high in many countries and in specific populations….[Yet] [h]igher pricing in an increasingly competitive market will ultimately translate into a missed opportunity to recoup development costs, and potentially better drugs will be barely used….So the compounds reviewed in this year’s ARV report—many with great potential—must be considered against a backdrop of a changing economic landscape. [1]

The good news is that use of high-quality generic ARV combinations has already enabled programs such as the U.S. President’s Emergency Program for AIDS Relief (PEPFAR) to treat three times as many people in 2012 as it did in 2008 despite flat funding levels. [2] Now, due to a coming wave of expiring ARV patents in rich countries, the possibility exists to save billions of dollars in HIV treatment costs by combining newly generic preferred ARVs with branded compounds—if the government and industry (both innovator and generic) collaborate to make the right products available; one paper estimated that if the United States switched to generic efavirenz, generic 3TC, and still-on-patent TDF, the country could save $920 million in the first year alone. [3] The FDA has already tentatively approved many of the right combinations for sale in developing countries, but it is not clear what the United States is doing to ensure that the cheap, high-quality drugs it’s providing to 5.1 million people in developing countries can also be made available to people here at home.

It will be critical for the United States—and for other programs such as Britain’s National Health Service (NHS)—to reinvest the savings generated by sensible use of generic-containing antiretroviral combinations into massively expanded HIV-prevention and treatment programs to end HIV transmission and progression to AIDS and death, and to achieve an “AIDS-free generation” in the United States and around the world.

The danger, as Collins and Horn point out, is that the world and even rich-country formularies will move even further toward two-tier ARV regimens, where the wealthy and those with private insurance will be able to access newer compounds which in some cases will be more tolerable and sometimes more durable than older regimens, while those receiving public-sector treatment in rich countries and nearly everyone in developing ones will receive older, suboptimal combinations (see “Seven Ways to Speed Up the Pipeline“).

Pediatric Antiretroviral Pipeline

In this year’s “Pediatric Antiretroviral Pipeline,” Polly Clayden notes that 2012’s “bumper year for ARV approvals” has been followed by one “in which new approvals were fewer and far between,” with “only two new…[U.S. FDA] approvals: an expanded indication for efavirenz to include children at least three months old, and once-daily dosing of darunavir in treatment-naive children three years and older,” while “[t]wo development programs—the granule formulation of ritonavir-based protease-inhibitor ritonavir, and the integrase inhibitor dolutegravir—remained attention-worthy.” [5]

While it took efavirenz 15 years from adult approval to reach very young children (there were admittedly formulation difficulties, and preclinical toxicology results of concern), it’s impressive that dolutegravir is already being studied in children, with a granule formulation in development for the youngest ones. In recent years, concerted efforts by a number of players including the Clinton Health Access Initiative (CHAI), the Drugs for Neglected Diseases Initiative (DNDi), and UNITAID, have stepped in to rationalize pediatric ARV access and development and drive it forward in a coordinated way.

Retrofitting for Purpose: Treatment Optimization

Lower doses of effective ARVs have the potential to be both more tolerable (in some cases) and cheaper (in most cases) than existing ones. As Clayden notes in “Retrofitting for Purpose: Treatment Optimization,” reformulation and process-chemistry efficiencies also have the potential to reduce the prices of common ARVs. [6] CHAI, the Bill & Melinda Gates Foundation, the Johns Hopkins University, Médecins Sans Frontières (MSF), the Medicines Patent Pool (MPP), and the WHO have been working on various strategies to this end since 2010. Clayden presents a wish list for an ideal ARV regimen [Table 1: Target product profile of a dream ARV regimen] and notes the plunging global best price of first-line fixed-dose combined efavirenz/3TC/TDF, which has dropped 21 percent in just one year, down to US$131 per person per year (pppy). (This is the combination that Walensky et al. found could save the U.S. health system $920 million dollars in the first year alone, and their model used the prior, 2012 price, so the actual savings are likely over $1 billion.) [3] The tenofovir prodrug, described here and by Collins and Horn, could potentially drive prices down further, since its active dose is 25 mg/day vs. 300 mg/day with TDF—and down to 10 mg/day when coadministered with cobicistat.

The WHO 2013 ARV treatment guidelines provide another opportunity for treatment optimization with simpler consolidated recommendations. [7] One concern, however, is that the WHO still includes lopinavir/ritonavir as a recommended second-line therapy (alongside atazanavir/ritonavir) while developed-country guidelines such as those in the United States prefer the more potent, durable, tolerable darunavir/ritonavir to the outdated lopinavir/ritonavir. At present, a heat-stable, generic combination darunavir/ritonavir product does not exist, which led to this decision, but with such products on the way, the WHO could rectify this oversight rapidly, and we recommend that they do so.

Clayden notes the potential for lower, cheaper dosing with TDF, zidovudine (AZT), efavirenz, atazanavir/ritonavir, darunavir/ritonavir, and boosting ritonavir itself. An outlier, stavudine (d4T), is being studied at a lower dose, but most activists and many clinicians oppose the continued use of this toxic relic of the 1990s. A recent agreement by UNITAID to subsidize the difference in cost between stavudine and TDF-containing regimens, in turn bringing the cost of TDF down still further, offers a way forward that will hasten the long overdue phasing-out of stavudine both in adults and—it is to be hoped—in children. [8]

Looking further ahead, Clayden notes the potential of new compounds such as low-dose, once-daily dolutegravir (50 mg/day) and—if provided as a single pill and at acceptable, affordable prices—the tenofovir prodrug TAF (25 mg/day, 10 mg/day if boosted with cobicistat) to bring down global ARV prices still further. Long-acting (LA) agents such as Shionogi/ViiV’s integrase follow-up compound, GSK1265744, and Janssen’s LA rilpivirine offer the possibility of monthly or even quarterly injectable dosing. [6]

Preventive Technologies, Research Toward a Cure, and Immune-Based and Gene Therapies

Richard Jefferys provides a sweeping overview of the complex developments in biomedical HIV preventive therapies, cure-related research, immune-based, cell and gene therapies. [9] For the first time ever, his broad chapter has yielded an FDA-approved product, FTC/TDF (Truvada) for prevention of sexually transmitted HIV. Uptake of the intervention—which is effective if taken daily—is hindered by the high price ($11,000 pppy or more in the U.S.) and by uncertainties about how best to use PrEP. Intermittent dosing studies are under way, as is a study of another agent, the CCR5 receptor blocker maraviroc, in an ongoing study among men who have sex with men (MSM). The long-acting ARVs mentioned above have the potential to work as PrEP, and microbicide researchers have turned to vaginal rings, which release anti-HIV agents slowly over a period of weeks. [9]

Vaccine research has seen impressive advances in basic science with the discovery of antibodies in chronically infected individuals that can neutralize an extensive array of clinical HIV strains. The work of turning this discovery into a candidate vaccine remains ahead. An injectable gene therapy–like approach, which appeared effective in mice and generates host resistance to HIV, is moving forward into human trials. Vaccine efficacy trials, however, are stalled after multiple reverses seen with adenovirus-vectored products, which in several trials appeared not only to be ineffective, but actually to increase incidence. [9]

Cure-related research generated many headlines, not always accurate, after a report at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI) demonstrated that an infant treated very early during infection, whose mother subsequently was lost to care in the chaotic health system of Mississippi, and whose treatment was therefore interrupted, appeared to have cleared HIV, lost antibodies to the virus, and be functionally cured. [10] Additional excitement was generated by a cohort of very-early-treated individuals in France who appear to have experienced long-term ART-free virological control for periods of up to several years. [11] These advances give additional impetus to ongoing efforts to design scalable, broadly usable, and safe therapeutic approaches that would produce a functional or sterilizing cure of HIV-1.

Jefferys notes that many immune-based and gene therapeutic approaches have now been subsumed under the cure-related research umbrella, but that two other potential indications remain understudied and potentially amenable to such therapeutic approaches—therapies that would increase immunologic recovery among INRs and those directed at sequelae of HIV infection that involve immuno-senescence and hyperimmune-activation-induced end-organ disease. [9]

2013 hepatitis C virus (HCV) pipeline executive summary

In “Hepatitis C Drug Development Catapults Onward,” Tracy Swan describes the astonishing therapeutic revolution currently under way in HCV treatment research:

Over the past 24 months, duration of treatment and assessment of posttreatment outcome have been dramatically abbreviated. Old-school, 48-week regimens with SVR-24 [sustained viral response 24 weeks after therapy ends] are gone. Now, duration of treatment is usually 12 to 24 weeks, and SVR-12 is the endpoint that is commonly used as a surrogate for cure….This acceleration in, and rapid evolution of, HCV drug development has left some drugs behind: they are shackled to lumbering development programs, such as the strategy being used in many phase III trials—adding a DAA [direct-acting antiviral] to 24 or 48 weeks of response-guided therapy with peginterferon (PEG-IFN) and ribavirin (RBV). This approach is likely to have limited clinical relevance, given the rapid development of peginterferon-sparing and peginterferon-free regimens.

The confluence of a robust HCV drug pipeline, shortened regimens, and posttreatment follow-up are extraordinary. The new FDA breakthrough therapy designation may speed things up as well. By the end of 2014, DAAs from four different classes and fixed-dose combinations (FDCs) are likely to be approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), offering the potential for off-label mixing and matching. [12]

HCV treatments in phases II or III include three nucleoside or nucleotide polymerase inhibitors, six non-nucleoside polymerase inhibitors, eight nonstructural 5A (NS5A) protein inhibitors, eight protease inhibitors, one microRNA targeting compound, and two fixed-dose combinations (FDCs) (see table 1). Two drugs—Janssen/Medivir’s once-daily protease inhibitor simeprevir and Gilead’s nucleotide polymerase inhibitor—were submitted to the FDA for expedited review in spring 2013, meaning that—barring unexpected surprises—they are likely to be approved before the end of the year. Their regulatory submissions, however, were suboptimal, and the combinations studied used ribavirin with or without peginterferon. By contrast, an astonishing 28 interferon-free regimens are in development for HCV genotype 1, with 11 under study for genotypes 2, 3, and 4 (see table 2).

Of necessity [see “Cross-company Trials“], some sponsors are codeveloping certain compounds in order to optimize outcomes, but others [13] are eschewing promising cross-company collaborations in order to develop combinations of their own molecules so as to seize market share regardless of whether their combinations are the best.

Swan’s command of the HCV pipeline is unparalleled, and anyone who wants to know what’s going on in the field needs to read her chapter. Research progress will not be reflected in public health advances, however, until and unless health systems adapt to meet the needs of the world’s 185 million people living with HCV.

The buck stops—and shrinks—when it comes to HCV treatment. The extortionate pricing of first-generation HCV protease inhibitors—added to the already high cost of peginterferon and ribavirin—limits treatment access even in wealthy countries. Oversight of complex treatment algorithms, frequent monitoring requirements during treatment, and management of nasty side effects add to the expense….The swift and astounding progress against hepatitis C virus will have a negligible impact on public health if medicines are too costly. In low- and middle-income countries (LMICs) millions of people with hepatitis C will go without treatments if governments cannot afford drugs, or the health care systems that will administer them. [1]

In “Low- and Middle-Income Countries Defuse Hepatitis C, the ‘Viral Time Bomb,'” Karyn Kaplan describes how a worldwide movement is forming to ensure that when new all-oral HCV cures are approved, that governments, health systems, and providers will be ready for them.

A growing movement of global activists is responding to this crisis…demanding access to affordable, quality drugs and diagnostics as well as high-level political commitment to testing and treatment scale-up in their countries. They will continue to fight until they defuse what the World Health Organization (WHO) has called the “viral time bomb.” [14]

enhance access to affordable treatment in developing countries….outrage that little has been done [since] to address the epidemic…has motivated a diverse coalition of stakeholders….A global movement for HCV treatment access has begun.

From Ukraine to India, and from Georgia to Egypt, activists from LMICs are adapting relevant lessons from the HIV treatment-access movement about how to reduce the cost of drugs and diagnostics, integrate services, and simplify the package of care. They are demanding that their governments take action to address local epidemics and include civil-society representatives meaningfully in the response. [3]

Some governments have stepped up to the challenge.

Egypt “developed the world’s largest nationally subsidized viral hepatitis–control program… [with] more than 220,000 people…already treated for hepatitis C.” [3] The country sponsored a local competitor to peginterferon to force Roche and Merck to lower prices—a tactic successfully used by Brazil over the years to reduce the price of expensive brand-name anti-HIV drugs.

Thailand responded to a multiyear activist campaign by making “a government commitment to expand HCV treatment access through the national health care program. In August 2012, Thailand put PEG-IFN on its national EML;” meanwhile “[t]he government, propelled by grassroots activists, successfully negotiated a significant [fourfold] price reduction from Roche and Merck: US$4,800 per treatment course.” [3]

Ukrainian activists protesting as “the Condemned” secured a government commitment to “develop a funded national plan.” [3]

Georgian activists and harm reduction advocates secured a commitment by Georgia’s Ministry of Corrections “to treat 300 people in prison who have HCV, expanding to 500 in the next year.” [3]

These victories show the way forward for activists from other low- and middle-income countries—and indeed for those from rich countries with deep disparities in health care access, such as the United States—who by using combinations of legal, political, scientific, media, and mass-mobilization strategies can bring the promise of all-oral cures to the 185 million people who will need them over the next decade.

2013 tuberculosis (TB) pipeline executive summary

Lack of investment and political will make the TB pipeline the most anemic covered in the 2013 Pipeline Report.

Globally, one-third of active TB cases are never diagnosed, reported, or treated, meaning that 3 million people are walking around with undiagnosed disease, in danger of progression, death, and onward transmission.

Recent advances in molecular diagnostics in the form of the Hain GenoType and Cepheid GeneXpert platforms for detecting drug-resistant forms of TB and, in the case of GeneXpert, diagnosing TB itself faster than any other test are, where available, helping to guide smarter treatment decisions. Hain, however, has recently doubled the price of its test kits, while Cepheid cannot keep up with demand for GeneXpert, in spite of a recent agreement with the President’s Emergency Plan for AIDS Relief (PEPFAR), UNITAID, USAID, and the Bill & Melinda Gates Foundation (BMGF) that dropped the price of its Xpert MTB/RIF test cartridges to below $10 apiece. In any case, a $17,000 test platform that needs to be returned annually to Toulouse, France, for calibration is never going to be used in field settings where most TB cases occur.

Several other companies are making molecular tests to compete with Xpert; some made in middle-income countries such as India have the potential to be cheaper, if they work. Regulatory standards are much lower for diagnostics than they are for drugs or vaccines, and few peer-reviewed data on these new molecular tests are available in the scientific literature.

Through the TB diagnostics research forum, the U.S. National Institute of Allergy and Infectious Diseases (NIAID) is teaming up with the Gates foundation, Stellenbosch University in South Africa, and others to expedite the development of more rapid molecular tests for TB organisms resistant to drugs such as pyrazinamide, the fluoroquinolones, and the newer batch of TB drugs coming through the pipeline.

Progress is slow. A urine dipstick made by Alere that diagnoses lipoarabinomannan (LAM), a TB surface protein, can add diagnostic specificity among people with HIV whose CD4 counts are below 100 cells/mm3, making this test a useful add-on in high-HIV burden areas where many people with advanced AIDS present for care. The test, however, is insensitive among the 85 percent of TB cases without HIV and among those on HIV treatment with CD4 counts above 100 cells/mm3.

Relatively small investments are under way to discover antibody or antigen targets for use in a point-of-care (POC) test, but none appear likely to turn up any time soon without greater investment.

Clinical research on new TB drugs and novel regimens, some containing mixtures of new and older drugs, is moving forward slowly. Forty years after last approving a new TB drug from a new class—rifampicin in the early 1970s—in December 2012, the U.S. Food and Health Administration (FDA) granted Janssen’s bedaquiline (TMC207, Sirturo) accelerated approval for treatment of drug-resistant TB. European approval is pending, and Janssen has filed in China, Russia, South Africa, and Thailand. Last month the World Health Organization (WHO) released early advice on how to use bedaquiline in developing countries. Despite its potency and ability to shorten time to culture conversion, many will await the results of further research before feeling comfortable using bedaquiline due to an unexpected mortality difference observed in one of the phase II studies, which were generally too small to reliably show whether this difference was a true drug effect or a statistical fluke.

Meanwhile Otsuka’s novel compound delamanid (OPC-67683) has been languishing at the European Medicines Agency (EMA) for over a year despite the drug’s evident safety, ability to shorten time to conversion in drug-resistant TB, and an apparent survival benefit among patients who received more than two months of the drug. The EMA does not seem to be aware that the European region has the highest burden of drug-resistant TB, and that new drugs and regimens to treat it are urgently needed.

The Global Alliance for TB Drug Development’s innovative new-combination trials NC-002 and NC-003 are moving along rapidly. Results are expected later this year. The Alliance has also proposed NiX-TB, a salvage trial for people with extensively drug-resistant (XDR) and pre-XDR-TB, using all-new compounds to which no resistance can have evolved. This study should start as soon as possible, as nearly one million people are living with drug-resistant TB and fewer than five percent of them are receiving appropriate treatment for the disease.

Several industry compounds are moving forward slowly. Pfizer seems to have virtually frozen clinical development of the new oxazolidinone sutezolid, which will be needed in the forthcoming trials of the NIAID-funded AIDS Clinical Trials Group (ACTG), the NiX-TB study, and the TB Alliance’s studies of novel TB regimens.

Regulatory agencies in developing countries are unprepared to deal with even one or two new TB regulatory submissions, let alone the new combination studies now being planned. They are also generally unfamiliar with pre-approval expanded access mechanisms such as compassionate use, requiring sponsors such as Janssen to create open-label safety studies among people with DR-TB. As we note elsewhere in this report, national regulatory authorities in developing countries must rapidly bring their capacity for 21st-century regulation up to par. Global bodies such as the WHO and technical partners such as the U.S. Centers for Disease Control and Prevention (CDC) and the FDA can help, but they too are suffering from the effects global financial austerity, and—in the United States—sequestration is hitting the CDC’s TB program and its research programs particularly hard.

Greater investment in the fundamental science of TB and its relation to the human host, and in vaccine discovery and development will be critical to developing new safe and effective TB vaccines that can prevent all forms of the disease. This research is moving forward slowly at this time due to a lack of investment.

Countries are doing a poor job of scaling up TB programs, particularly for people with drug-resistant, HIV-associated, or pediatric disease. The Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) has awarded countries US$2 billion to scale up TB programs in the coming two years, but many countries have been unable to deliver the promised scale-up. There is a danger that these funds committed to TB may be shifted to more successful HIV or malaria programs if in-country TB programs continue to fail their populations. This bodes poorly for the forthcoming GFATM replenishment meeting next year, at least for TB.

Ongoing stock-outs of key first-line drugs such as isoniazid and rifampicin and second-line drugs such as amikacin and kanamycin, as well as of assays such as tuberculin skin testing, continue to occur in developing countries as well as the United States. The underlying the lack of political will, and the failure to project program needs and to deliver the right drugs to the right patients at the right time, indicate that despite having a burden of disease almost as great as HIV, and a death rate to match, TB remains far too low on the world’s political or scientific agenda. This must change, or millions of unnecessary cases of TB and deaths from the disease will continue to occur over the coming years and decades.

2013 HIV pipeline recommendations

Adult Antiretroviral Pipeline

The demand for ARVs is well established, and it will continue to expand for many years: life expectancy has been dramatically extended; treatment is lifelong and is now being recommended regardless of a person’s CD4 T-cell count; rates of new infections and diagnoses remain high in many countries and in specific populations; and even optimistic reviewers see advances toward a cure as a long-term goal, at least a decade away. [1]

Restricted budgets for most health care systems and steadily approaching patent expiries for several commonly used ARVs mean that new drugs also need to match or undercut existing products on price to earn their place as better treatments. When a new product’s efficacy, safety, and dosing convenience are broadly similar to those of currently used ARVs, the drug price increasingly determines use. Higher pricing in an increasingly competitive market will ultimately translate into a missed opportunity to recoup development costs, and potentially better drugs will be barely used. [1]

The forthcoming introduction of dolutegravir, with its multiple advantages including impressive clinical trials data, low molecular weight, single daily dosing, and lack of need for boosting, gives its sponsor, ViiV Healthcare, a chance to price the drug competitively (e.g., lower than existing integrase inhibitors) to broaden access to this class, potentially changing globally recommended first- and/or second-line preferred regimen choices. “To date, integrase inhibitors as a class have been a good example of the pitfalls of inappropriate pricing. After more than a decade of careful and intensive research, the first integrase inhibitor was approved over five years ago. But the potential global benefits from this new class, given their impressive results, have hardly been realized because of premium pricing.”1 Both raltegravir and elvitegravir (approved last year as part of Stribild) have been too expensive to make an impact globally.

“Savings from generics are essential if we are to retain public health services for those who remain uninsured or underinsured.” [1] Generic manufacturers and governments must seize the opportunity posed by the coming wave of patent expiries to offer optimal combinations (either fixed-dose or blister-pack) at prices much lower than for innovator compounds. It will be critical for the United States—and for other programs such as Britain’s National Health Service (NHS)—to reinvest the savings generated by sensible use of generic-containing antiretroviral combinations into massively expanded HIV prevention and treatment programs to end HIV transmission and progression to AIDS and death and achieve an “AIDS-free generation” in the United States for everyone.

Innovator companies must ensure that novel compounds are studied and made available on the market as single pills as well as in fixed-dose combinations (FDCs) to enable people with HIV to assemble optimal combinations based on their own needs. Thus, Gilead needs to ensure that elvitegravir, cobicistat, and—when available—tenofovir alafenamide (TAF) are each available as single pills to maximize patient and provider choice. This is particularly critical for TAF. The current development plan will not inform its use outside Gilead’s FDCs, which rely on a pharmacokinetic interaction with cobicistat to determine the dose under investigation.

Governments, donors, guidelines panels, innovator and generic companies, providers, independent investigators, people with HIV and activists must work together to ensure that the best drugs and combinations are available for all, regardless of date of market entry, patent expiry, or individual manufacturer. The ongoing emergence of some dual-sponsor fixed-dose combinations is meritorious and should be expanded to allow the combination of generic and innovator compounds as expeditiously as possible to enable the best therapeutic options to be provided.

People with HIV resistant to three classes of drugs or more need new treatment options, which will require regulatory flexibility in developed countries and greater access to third-line therapy in developing ones. Recent moves by the FDA [3] to define a registration path for treatment of multidrug-resistant HIV, ongoing consultations among FDA and the HIV community [4] and the inclusion by WHO in its new consolidated HIV treatment guidelines [16] of recommendations for third-line antiretroviral therapy (ART) are necessary, but not sufficient, steps in the right direction.

Pediatric Antiretroviral Pipeline

To repeat from the 2012 Pipeline Report: there is a danger of pediatric HIV becoming an old story against a backdrop of targets to eliminate vertical transmission by 2015, which though they are laudable, must not happen at the cost of continual scale-up for children. And back to the reality check: currently only 28 percent of children with HIV in need of treatment are receiving it. [17] Most of what is recommended below is spillover from previous years, but unfortunately has not been done yet. [18]

The new WHO guidelines for treating children strike a fairly good balance between aspirational and pragmatic. It is important that nevirapine-containing regimens still remain an alternative as the recommended lopinavir/ritonavir first-line regimens (including for rural neonates) will frequently not be feasible with the formulation currently available. If recommendations become too complex, children often do not receive anything. As a simpler formulation of lopinavir/ritonavir becomes available, countries must ensure that it is swiftly approved and distributed, with appropriate training for health workers.

Other missing formulations needed to implement the guidelines must be made available. If the market is too tiny to interest generic companies, donors need to step in to support this.

The news of the infant with a “functional cure” provoked much discussion. Researchers and implementers are already planning pilot programs and studies to advance research findings. The news should stimulate all programs to do infant PCR as early as possible and intensify post exposure prophylaxis (or early treatment) for neonates of at risk pregnancies (not to mention identifying and treating pregnant women). Successes must be followed by rapid advice from the WHO.

Support new models of research and development. There is a lot of hope resting on the successful development and delivery of the Drugs for Neglected Diseases Initiative (DNDi) product. That an initiative focusing on diseases of the poor has selected pediatric HIV as a focus speaks volumes. More innovative models of research and development, and appropriate agreements between originator companies and generic ones to produce child-adapted formulations in a timely fashion must be made.

Ensure that patents are not an obstacle. The Medicines Patent Pool (MPP) is putting a lot of emphasis on pediatric antiretrovirals. Even the most hesitant innovator companies, as far as adult drugs are concerned, must recognize that pediatrics will never be much of a market let alone a moneymaker. Gilead’s license agreement with the MPP always has royalties waived for any new pediatric formulations. [19] ViiV will grant MPP a voluntary license for pediatric formulations of abacavir. [12, 20] There is also a commitment to do the same for dolutegravir. Other companies must follow suit and is very important to ensure availability beyond sub-Saharan Africa. What AbbVie decides to do about the lopinavir/ritonavir granules will be closely watched.

Rationalize available formulations. Development, approval, and distribution of new formulations need to happen in ways that are timely and do not further fragment the market. The time from first approval to when products are available where they are most needed must shorten. This will require earlier access by generic companies to new products (which must include the possibility to develop FDCs with components from different innovators) and registration by the WHO and in-country. To reduce the current situation with too many formulations and too few real options, products need to be rationalized, and unsuitable ones phased out.

Consolidate procurement. CHAI needs to continue with its successful model of price negotiations. [21] Concerted efforts by international donors, including the Global Fund and PEPFAR, need to be made to facilitate the transition from previous reliance on UNITAID funding of pediatric products. In the many individual countries where orders do not meet manufacturer volume requirements, buyers must get together.

Retrofitting for Purpose: Treatment Optimization Pipeline

Treatment optimization must be in the interests of people with HIV.

Trials like the one of low-dose stavudine, conducted for the sake of cost alone, and against much opposition from people with HIV and activists, are unacceptable. Activist and patient acceptability is always important. This will become increasingly true as indications for starting become broader, and more asymptomatic people with HIV are offered treatment.

Drugs and regimens need to be designed with resource-limited settings in mind. The target product profile has been widely described by now. Currently approved and pipeline compounds fit for this purpose need to be studied and produced in appropriate formulations.

The time between full FDA/EMA approval and WHO prequalification, FDA tentative approval of generics in association with PEPFAR’s expedited review process, and approval by local regulatory agencies must be shortened.

Eliminate the delay between availability of the best new drugs and combinations in one country and their availability everywhere. Delays with the registration process, in addition to production by generic manufacturers and recommendations in national guidelines, means that it takes years from promising results in trials and initial approval to wide availability for the majority of people in need of antiretroviral treatment. Despite over 150 single agents and combination products having FDA tentative approval, the majority are older drugs and those with expired patents. [7]

Preventive Technologies, Research Toward a Cure, and Immune-Based and Gene Therapies

Basic and translational science on potential HIV vaccines must continue, incorporating the best scientific understanding of new developments in basic science, and learning from recent setbacks.

Research on antiretroviral-based pre- and postexposure prophylaxis (PrEP and PEP) must continue as a high priority, with attention given both to optimizing delivery methods (e.g., long-acting parenteral or barrier delivery systems) as well as understanding how best to use newly licensed approaches such as TDF/FTC PrEP to reduce new HIV infections in the real world.

Immune-based therapy research must continue to explore the possibilities of improving immunologic recovery among immunologic nonresponders (INRs).

New research is needed to address ongoing “residual dysfunction of the immune system that can persist in individuals on ART, [including] elevated levels of inflammation and features resembling the age-related immunologic wear and tear seen in the elderly.” [9]

Given the overwhelming efficacy of existing strategies for prevention of mother-to-child transmission (PMTCT) with antiretroviral therapy (ART), an independent panel of the Institute of Medicine (IOM) should review proposed studies of passive immunization for this purpose before they are undertaken.

Following up on the intriguing results presented by Persaud at CROI 2013 and by the VISCONTI cohort, research should further investigate the role of very early treatment with potent antiretroviral therapy (ART) combinations in both infants and adults infected with HIV.

Research is needed to better understand and quantify the cells and tissue sources of the latent HIV-1 infected cell reservoir, which is the target for HIV cure research, and to enable the development of assays, which can be automated and used to quantify the effects of potential curative therapy approaches on the size and dynamics of the reservoir.

The potential contribution of therapeutic vaccine approaches as part of combination curative therapy needs to be further explored.

Funders, manufacturers, and researchers conducting research which may be relevant to potential HIV curative approaches should carefully modulate their public statements and presentations to ensure that they contain accurate scientific information rather than hype and speculation.

Current funding limitations on basic, vaccine, prevention, and cure-related research on HIV infection must be overcome or all the potential promise of the coming years will be deferred or denied, potentially extending the toll of the pandemic deep into the current century.

2013 hepatitis C virus (HCV) pipeline recommendations

HCV Treatment and Research Pipeline

Regulators, activists, patient groups, and legislators need to revisit the design of early access programs, and create a framework to allow access to potentially lifesaving treatment for people who are too ill or otherwise ineligible for clinical trials, while safety and efficacy data are collected.

Governments, pharmaceutical companies, and foundations should support public-private research networks, and civil-society representatives should participate in development and oversight of these networks.

Regulatory agencies need to identify metrics that will facilitate reimbursement for off-label use, keeping in mind both class-specific and within-class-specific differences in drug potency, resistance barrier, safety, and side effects profile.

Regulators, clinicians, and other stakeholders should discuss requirements for HCV drug development, given the rapid evolution of HCV treatment.

HCV Policy and Access

These changes are required to achieve universal access to high-quality HCV prevention and treatment services:

Governments must immediately repeal laws that criminalize people who use drugs. These laws perpetuate unsafe injection practices and drive people underground and away from essential health services. [22]

Governments, in partnership with civil society, must create and fully fund national plans that address concentrated and generalized hepatitis C epidemics.

Merck and Roche must drastically reduce the price of PEG-IFN in low- and middle-income countries. Currently, treatment cost can exceed the per capita gross domestic product (GDP) by over tenfold. [23]

The WHO, the European Medicines Agency (EMA), and the U.S. Food and Drug Administration (FDA) must create a clear and harmonized regulatory pathway for biosimilars. The WHO must clarify, simplify, and streamline the prequalification process for biosimilar products (and diagnostics). In turn, biosimilar manufacturers should collect appropriate data and be transparent with regulatory agencies.

Donor agencies must support development of simple, accurate, and affordable HCV diagnostics and disease-staging tools, since their cost and complexity are major barriers to treatment.

2013 tuberculosis (TB) pipeline recommendations

TB Diagnostics Pipeline

Funding

Donors must increase funding and work to bring more scientists and innovators into the field to develop an optimal point-of-care TB test that is affordable, patient- and user-friendly, accurate in people with any form of TB, and will result in TB treatment decisions in one visit or encounter.

The private sector and middle-income countries need to increase investment in TB diagnostics development. The BRICS countries (Brazil, Russia, India, China, and South Africa) must increase their investment in TB R&D for new tools as well as the infrastructure to evaluate and demonstrate their field-effectiveness.

Biomarkers

Donors must prioritize increased investment in basic science to quantify biomarkers as surrogate clinical endpoints for clinical trials of new drugs, regimens, and vaccines.

DST

Donors must fund and prioritize decentralized DST for fluoroquinolones, pyrazinamide, and other drugs, particularly second-line drugs.

Country programs and donors must implement the recommendation to do rapid DST of isoniazid and rifampicin, or of rifampicin alone, over conventional testing or no testing at the time of diagnosis of TB.

Donors and industry must work to develop universal DST and newer DST methods to rapidly identify regimens to which every patient’s bacterial organism is susceptible.

Specimen bank

Donors need to fund repositories of useful, viable specimen samples that are available openly and freely.

Policies and strategies

Donors, national programs, and implementers must develop policies and strategies that move toward active case-finding and integrate TB services across the health system.

Donors and national programs must integrate new TB diagnostic tools such as Xpert MTB/RIF into HIV-, maternal and child–, and other health care services wherever possible.

Programs must work to develop national strategies that allow the flexibility to introduce any new tool or regimen whenever available and needed.

Regulatory agencies must develop stringent evidentiary standards for the introduction of new diagnostic tests to ensure that people have access to good, accurate tools without delay.

Programs in countries with high HIV burdens should assess the usefulness of tests that have not yet been endorsed by international agencies, in their own settings, particularly where TB kills many people before they are even diagnosed.

National programs should not wait for the WHO to make recommendations regarding the use of tools if they have the resources to do so themselves. However, programs should beware of promotional marketing by diagnostics developers that lacks supporting data.

Donors, in particular BRICS and other middle-income countries, must conduct operational research to determine at how low a level of the health system Xpert could be implemented.

Donors, industry, and national programs must develop policies that make good tests more affordable to all sectors, public and private.

UNITAID, the BMGF, PEPFAR, USAID, and the WHO must ensure that Cepheid identifies the causes of Xpert cartridge shortages and fixes them quickly.

TB Treatment Pipeline

Governments and donors need to increase funding for TB research at least threefold. Countries with high rates of TB, particularly middle-income ones such as the BRICS, must invest more in TB R&D. [24]

Sponsors must commit to developing their drugs and making them accessible to other research groups. In particular:

AstraZeneca should continue to invest in AZD5847, and begin to engage with community groups;

Janssen must quickly fulfill its postmarketing requirements for bedaquiline, and work to close other research gaps including potential drug-drug interactions with delamanid and other drugs, and dosing and safety concerns in special populations including children;

Novartis needs to make clofazimine available for TB research studies;

Otsuka should facilitate the NIH’s interaction work combining delamanid with bedaquiline to ensure this key study advances as quickly as possible;

Pharmasyntez needs to make its full data available for peer review and create a sound, responsible development plan for perchlozone before pursuing further research studies or registration;

Pfizer must commit to developing sutezolid and making it available to research consortia for developing optimized combinations;

Sanofi should maintain its support for the CDC-funded TB Trials Consortium (TBTC) to enable further research on rifapentine amid public financial austerity; and

Sequella should be more transparent and amenable to sharing SQ109 data so its suitability for further development can be appropriately assessed.

More research is needed in vulnerable populations. TB drug sponsors and researchers must commit to studying TB drugs as thoroughly as possible, and as quickly as safety allows, in children, women (including pregnant women), people with HIV, people with hepatitis B and C, people who use alcohol, and people who inject drugs or are on opioid substitution therapy. Regulatory authorities can play an important role by appropriately encouraging and providing incentives for research in these populations.

The TB community needs to collaborate to develop an efficient path for testing new drugs and determining optimal combinations.

Regulatory authorities must build capacity and expertise to appropriately regulate clinical trials, early access, accelerated approval, postmarketing studies, and pharmacovigilance for new TB drugs and regimens. Regulatory agencies—particularly those in high-TB-burden countries—must scale up their ability to rapidly and carefully review submissions, and enforce conditions of approval. The Russian Federation and the Confederation of Independent States (CIS) in particular must improve their review processes to ensure that studies, especially registration trials, are appropriately designed and conducted, and that only drugs with robust and peer-reviewed data on safety, efficacy, and dosing receive marketing approval.

National TB programs need to improve their services, supply-chain management, and ability to rapidly adopt and appropriately implement new tools.

Drug sponsors and manufacturers must make licensed drugs accessible and affordable. In particular:

Janssen should continue to file for approval in a range of countries, and price bedaquiline accessibly.

Otsuka’s compassionate use program for delamanid is overdue and needs to be initiated immediately, as it will likely be over a year until the drug is commercially available.

Pfizer needs to lower the price of linezolid.

Sanofi should quickly lower the price of rifapentine to enable the taxpayers who funded its development to benefit from its implementation.

TB Vaccine Pipeline

Prioritize the science behind biomarker discovery to determine correlates of risk of TB acquisition, disease progression, response to therapy, as well as correlates of immune protection via innate or acquired immunity, including postvaccination. [25, 26, 27]

Develop and validate a human challenge model for TB infection and disease. [28,29]

World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. Geneva: World Health Organization; forthcoming 2013 June 30. Available 2013 June 30 from:http://www.who.int/hiv/pub/arv/en/index.html.